Cellular &Molecular Immunology最新文献

The use of TNF inhibitors (TNFis) has revolutionized the management of rheumatoid arthritis (RA) and other autoimmune conditions, but some patients remain resistant to TNFis, for which the molecular mechanisms remain elusive. Our study reveals novel molecular crosstalk between TWEAK/Fn14 and TNF-α signaling and its potential implications for therapy resistance. Elevated Fn14 expression was observed in human synovial tissues and joint homogenates from adjuvant-induced arthritis rats. Low doses of TNF-α and TWEAK synergistically induced inflammation in human RA synovial fibroblasts (RASFs). Furthermore, increased expression of the TWEAK receptor (Fn14) was sufficient for TNF-α to synergistically induce RANTES/CCL5 and MMP-1. In contrast, Fn14 knockdown suppressed the expression of TNF-α-induced adhesion molecules (PDPN, ICAM-1, VCAM-1, and cadherin-11) and inflammatory chemokines (MCP-1/CCL2, RANTES/CCL5, IL-8/CXCL8, and ITAC/CXCL11). Blocking Fn14 with an antagonist (L524-0366) suppressed TNF-α-induced phosphorylation of the kinases JNK, p38, and PKCδ and consequently decreased MCP-1/CCL2, RANTES/CCL5, ITAC/CXCL11, and MMP-1 production. RNA-sequencing analysis revealed >200 differentially expressed genes significantly affected by Fn14 knockdown in TNF-α-activated RASFs. Gene set enrichment analysis (GSEA) revealed significant enrichment of IFN-α and IFN-γ pathway responses in the NC siRNA/TNF-α group compared with the Fn14 siRNA/TNF-α group. Administration of L524-0366 (10 mg/kg) intraperitoneally daily from the onset of disease ameliorated collagen antibody-induced arthritis in mice. These findings reveal that TNF-α utilizes the TWEAK/Fn14 axis to induce inflammation, suggesting the potential benefits of targeting TWEAK/Fn14 as an adjunct therapy with TNF inhibitors.

Despite the pleiotropic capacities of cytokines in modulating cell behaviors, their therapeutic application in cancer remains challenging. Here, we show that the IFN-γ/IFN-β/TGF-β cocktail integrates these three signals with a cytosolic pore-forming protein, gasdermin E (GSDME), and synergistically drives its delivery into the lysosomes of pancreatic adenocarcinoma (PDAC) tumor-repopulating cells (TRCs), where GSDME is cleaved to mediate lysosomal pore formation. Mechanistically, IFN-γ signaling phosphorylates GSDME, enabling phosphorylated GSDME (p-GSDME) to bind the Golgi transmembrane protein TMED10 and subsequently traffic to lysosomes, where cathepsin D cleaves it into active N-GSDME, which induces lysosomal decomposition in TRCs. In parallel, IFN-β activates STAT1/STAT3 to upregulate cathepsin D expression, whereas TGF-β enhances GSDME phosphorylation by downregulating PPP1R3G, a regulatory subunit of protein phosphatase 1. Using lipid-hybrid nanoparticle-delivered mRNA technology, the tri-cytokine cocktail demonstrated therapeutic efficacy against orthotopic PDAC in mice and PDX models, highlighting its translational potential for PDAC patients.

Cuproptosis, a recently identified copper-dependent form of regulated cell death, is driven by mitochondrial dysfunction caused by copper overload. Cuproptosis results from proteotoxic stress, which is triggered by copper-induced aggregation of lipoylated tricarboxylic acid (TCA) cycle enzymes and destabilization of iron-sulfur cluster proteins. This review elucidates the mechanisms of cuproptosis, emphasizing its regulation by copper homeostasis, metabolic reprogramming, and key signaling pathways such as p53, HIF-1α, Wnt/β-catenin, and AKT. Notably, copper modulates antitumor immunity through its effects on the tumor microenvironment, suggesting a critical role in cancer immunotherapy. Therapeutic strategies using copper ionophores and nanomedicine platforms demonstrate potential to induce cuproptosis in a variety of cancers. Preclinical studies highlight cuproptosis as a promising strategy against malignancies with copper dysregulation or mitochondrial metabolism adaptation, while clinical translation requires biomarker-driven patient stratification and optimized delivery systems. This synthesis provides a framework for harnessing cuproptosis in precision oncology, bridging mechanistic insights to therapeutic innovation.

Group 2 innate lymphoid cells (ILC2s) play crucial roles in maintaining adipose tissue homeostasis. Recent studies indicate that ILC2s are dysregulated in obesity. However, the regulatory mechanisms governing adipose tissue ILC2 function remain inadequately explored. In this study, we demonstrated that mechanistic target of rapamycin complex 1 (mTORC1) activity is impaired in adipose tissue ILC2s from obese mice and humans. Deletion of Raptor, a critical adaptor protein in mTORC1, results in reduced numbers of ILC2s and diminished type 2 cytokine production in ILC2s, leading to increased adipose tissue inflammation and insulin resistance. Mechanistically, mTORC1 signaling upregulates PPARγ expression through HIF-1α, which promotes mitochondrial biogenesis and ST2 expression to sustain ILC2 metabolic and functional fitness. Together, our data identify mTORC1 as a crucial regulator that coordinates adipose tissue ILC2 metabolic and immunological homeostasis and prevents obesity-associated insulin resistance.

Tumor-associated macrophages (TAMs) play crucial roles in tumor progression. However, the mechanisms underlying the posttranscriptional regulation of TAMs remain largely unknown. Here, we demonstrated that Trmt61a, the "writer" enzyme of tRNA N1-methyladenosine (m¹A) modification, is highly expressed in proinflammatory macrophages in tumor microenvironment. We generated conditional knockout (KO) mice for Trmt61a and observed that Trmt61a deletion in macrophages significantly promoted tumor growth. Mechanistically, we identified that m¹A maintains the translation of STING, enhances STING-TBK1-IFN-β signaling in macrophages and therefore suppresses tumor cell growth. We further generated TRMT61A-overexpressing human iPSC-derived CAR-macrophage and demonstrated that human TRMT61A effectively promoted antitumor CAR-macrophage therapy in vivo. Collectively, our findings reveal a novel regulatory mechanism of tRNA m¹A modification in macrophages, highlighting the antitumor therapeutic potential of targeting tRNA m¹A modification in macrophages.

Excitatory amino acid transporters (EAATs) mediate the progression of inflammatory diseases. However, the involvement of EAATs in the activation of mast cells (MCs) and MC-associated diseases remains unclear. Here, we demonstrate that EAAT2 expression (encoded by Slc1a2) directed by immunoglobulin E (IgE)-mediated high-affinity IgE receptor (FcεRI)-p38 signaling is indispensable for MC degranulation through osteopontin (OPN, encoded by Spp1). Mechanistically, EAAT2 regulates intracellular glutamate/alpha-ketoglutarate/reactive oxygen species (ROS) metabolism to reduce the DNA and histone H3K9 methylation of Spp1. Most importantly, MC-specific depletion of Slc1a2 alleviates the allergic response in mice, and EAAT2 expression is positively correlated with MC-associated diseases in humans. Taken together, our findings establish a mechanistic link between amino acid transporters and epigenetic modifications with MC activation and provide potential therapeutic targets for allergic diseases.

The precise control of type I interferon (IFN-I) signaling is critical for effective antiviral defense and the maintenance of immune balance. In this study, we revealed a dynamic regulatory network involving lactylation-delactylation of TANK binding kinase 1 (TBK1), a pivotal kinase of IFN-I signaling, that finely tunes antiviral immune responses. Viral infection triggers the lactylation of TBK1 at K241, which is mediated by alanyl-tRNA synthetase 1 (AARS1), which potentiates IFN-I signaling to establish an antiviral state. Notably, we identified sirtuin 6 (SIRT6) as a pivotal "eraser" responsible for reversing this process by removing TBK1 lactylation. This action initiates a stringent negative feedback loop, leading to delactylated TBK1 being targeted by the E3 ligase SIAH2 for K48-linked polyubiquitination and subsequent selective autophagic degradation via p62. In vivo experiments revealed that myeloid-specific deletion of Sirt6 in mice resulted in sustained TBK1 lactylation and increased IFN-I production during VSV infection, ultimately improving survival. This intricate regulatory circuit not only maintains an appropriate IFN-I response to prevent excessive immune activation but also highlights the potential of targeting lactylation as a novel therapeutic strategy for chronic infections and autoimmune diseases associated with TBK1 dysregulation.